Method and apparatus for location and temperature specific drug action such as thrombolysis

ABSTRACT

A method is provided of localizing a drug action where the drug is present throughout a vascular system. The localization occurs to within a volume of blood in a blood vessel, the vascular system having an initial temperature substantially within a first temperature range. A temperature-specific enzyme is delivered throughout a vascular system including a volume of blood in a blood vessel, the temperature-specific enzyme having a working temperature within a prespecified temperature range that does not substantially overlap the first temperature range. A heat transfer element is delivered to a blood vessel in fluid communication with the volume of blood. The temperature of the heat transfer element is adjusted such that the volume of blood in the blood vessel is heated or cooled to the prespecified temperature range. In this way, the action of the temperature-specific enzyme is substantially limited to the volume of blood heated or cooled. In an alternative embodiment, the temperature-specific enzyme is localized to the volume of blood in the blood vessel, and the heat transfer element is disposed in fluid communication with the volume of blood in the blood vessel. The enzyme localization may occur by way of direct injection or by way of injection through a lumen of a catheter. The injection lumen of the catheter may be disposed at least partially adjacent or in combination with the heat transfer element and its associated inlet and outlet lumens.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part patent application of co-pending U.S.patent application Ser. No. 09/215,039, filed Dec. 16, 1998, andentitled “Method for Low Temperature Thrombolysis and Low TemperatureThrombolytic Agent with Selective Organ Temperature Control”; U.S.patent application Ser. No. 09/215,040, filed Dec. 16, 1998, andentitled “Method and Device for Applications of Selective OrganCooling”; U.S. patent application Ser. No. 09/103,342, filed Jun. 23,1998, and entitled “Selective Organ Cooling Catheter and Method of Usingthe Same” U.S. Pat. No. 6,096,068; U.S. patent application Ser. No.09/047,012, filed mar. 24, 1998, and entitled “Selective OrganHypothermia Method and Apparatus” U.S. Pat. No. 5,957,963; and U.S.patent application Ser. No. 09/052,545, filed Mar. 31, 1998, andentitled “Circulating Fluid Hypothermia Method and Apparatus”.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the modification and controlof optimal temperatures for enzymes. More particularly, the inventionrelates to the modification and control of optimal temperatures forenzymes for use in treatments such as thrombolysis.

2. Background Information

Organs in the human body, such as the brain, kidney and heart, aremaintained at a constant temperature of approximately 37° C. Hypothermiacan be clinically defined as a core body temperature of 35° C. or less.Hypothermia is sometimes characterized further according to itsseverity. A body core temperature in the range of 33° C. to 35° C. isdescribed as mild hypothermia. A body temperature of 28° C. to 32° C. isdescribed as moderate hypothermia. A body core temperature in the rangeof 24° C. to 28° C. is described as severe hypothermia.

Hypothermia is uniquely effective in reducing brain injury caused by avariety of neurological insults and may eventually play an importantrole in emergency brain resuscitation. Experimental evidence hasdemonstrated that cerebral cooling improves outcome after globalischemia, focal ischemia, or traumatic brain injury. For this reason,hypothermia may be induced in order to reduce the effect of certainbodily injuries to the brain as well as other organs.

Cerebral hypothermia has traditionally been accomplished through wholebody cooling to create a condition of total body hypothermia in therange of 20° C. to 30° C. However, the use of total body hypothermiarisks certain deleterious systematic vascular effects. For example,total body hypothermia may cause severe derangement of thecardiovascular system, including low cardiac output, elevated systematicresistance, and ventricular fibrillation. Other side effects includerenal failure, disseminated intravascular coagulation, and electrolytedisturbances. In addition to the undesirable side effects, total bodyhypothermia is difficult to administer.

Catheters have been developed which are inserted into the bloodstream ofthe patient in order to induce total body hypothermia For example, U.S.Pat. No. 3,425,419 to Dato describes a method and apparatus of loweringand raising the temperature of the human body. Dato induces moderatehypothermia in a patient using a metallic catheter. The metalliccatheter has an inner passageway through which a fluid, such as water,can be circulated. The catheter is inserted through the femoral vein andthen through the inferior vena cava as far as the right atrium and thesuperior vena cava. The Dato catheter has an elongated cylindrical shapeand is constructed from stainless steel. By way of example, Datosuggests the use of a catheter approximately 70 cm in length andapproximately 6 mm in diameter. However, use of the Dato deviceimplicates the negative effects of total body hypothermia describedabove.

Due to the problems associated with total body hypothermia, attemptshave been made to provide more selective cooling. For example, coolinghelmets or head gear have been used in an attempt to cool only the headrather than the patient's entire body. However, such methods rely onconductive heat transfer through the skull and into the brain. Onedrawback of using conductive heat transfer is that the process ofreducing the temperature of the brain is prolonged. Also, it isdifficult to precisely control the temperature of the brain when usingconduction due to the temperature gradient that must be establishedexternally in order to sufficiently lower the internal temperature. Inaddition, when using conduction to cool the brain, the face of thepatient is also subjected to severe hypothennia, increasing discomfortand the likelihood of negative side effects. It is known that profoundcooling of the face can cause similar cardiovascular side effects astotal body cooling. From a practical standpoint, such devices arecumbersome and may make continued treatment of the patient difficult orimpossible.

Selected organ hypothermia has been accomplished using extracorporealperfusion, as detailed by Arthur E. Schwartz, M.D. et al., in IsolatedCerebral Hypothermia by Single Carotid Artery Perfusion ofExtracorporeally Cooled Blood in Baboons, which appeared in Vol. 39, No.3, NEUROSURGERY 577 (September, 1996). In this study, blood wascontinually withdrawn from baboons through the femoral artery. The bloodwas cooled by a water bath and then infused through a common carotidartery with its external branches occluded. Using this method, normalheart rhythm, systemic arterial blood pressure and arteial blood gasvalues were maintained during the hypothermia. This study showed thatthe brain could be selectively cooled to temperatures of 20° C. withoutreducing the temperature of the entire body. However, externalcirculation of blood is not a practical approach for treating humansbecause the risk of infection, need for anticoagulation, and risk ofbleeding is too great. Further, this method requires cannulation of twovessels making it more cumbersome to perform particularly in emergencysettings. Even more, percutaneous cannulation of the carotid artery isdifficult and potentially fatal due to the associated arterial walltrauma. Finally, this method would be ineffective to cool other organs,such as the kidneys, because the feeding arteries cannot be directlycannulated percutaneously.

Selective organ hypothermia has also been attempted by perfusion of acold solution such as saline or perflourocarbons. This process iscommonly used to protect the heart during heart surgery and is referredto as cardioplegia. Perfusion of a cold solution has a number ofdrawbacks, including a limited time of administration due to excessivevolume accumulation, cost, and inconvenience of maintaining theperfusate and lack of effectiveness due to the temperature dilution fromthe blood. Temperature dilution by the blood is a particular problem inhigh blood flow organs such as the brain.

Selective organ hypothermia is useful in limiting brain injury afterischemia or traumatic brain injury, as noted above. For example, neuronssubjected to ischemia may die. Selective cooling of these neurons, suchas by nerve cooling, has been shown to increase the survival rate.Hypothermic temperatures which may be employed include, e.g., 20° C. to35° C.

Ischemia is blockage of the arteries that supply blood to a tissue. Theblockage itself is referred to as a clot or thrombus and results fromthe solidification of fibrinogen into fibrin. A stroke is ischemia wherethe arteries to the brain are blocked. In a stroke, the clot forms inthe cerebral or pre-cerebral arteries. This type of blockage may also becaused by a thrombus that breaks free from the heart and flows into anartery through which it cannot pass. In other words, the thrombus getslodged in the artery. Clots can be treated in several ways. One way,fibrinolysis, employs enzymes that lyse, or break up and dissolve, theclot. Thrombolysis is fibrinolysis used to treat thrombosed vessels. Theenzymes that lyse clots are termed thrombolytics because thrombin is theenzyme that coagulates fibrinogen. Streptokinase (“SK”), urokinase(“UK”), and tissue plasminogen activator (“tPA”) are thrombolytics andare often used in this capacity. These enzymes can be given as drugs byintravenous injection orby intra-arterial delivery using a catheter witha fluid outlet port near or at the site of the clot. Drug administrationis occasionally problematic as some sensitive patients encounter adversereactions to drugs. Moreover, there is a risk of hemorrhage when thesedrugs are given intravenously. There is a need for a method of lysingclots that does not rely solely or partially on drug administration.There is further a need for a method of lysing clots in which theeffects of ischemia on affected cells is minimized.

In some cases, of course, the extent or nature of the clot indicatesthat drug therapies must be used. The effectiveness of drug therapies isdependent on several factors, including the temperature of theenvironment in which the drug acts. Thus, there is further a need for adrug therapy which is effective to treat a thrombus and which is alsocomplementary to efforts to reduce ischemia, especially when thoseefforts employ hypothermia.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the invention relates to a method for substantiallyreducing the size of a thrombus in a blood vessel. The method includesdelivering a heat transfer element to a blood vessel in fluidcommunication with a thrombosed blood vessel. The temperature of theheat transfer element is adjusted such that the same is sufficient toremove heat from the flowing blood. Heat is transferred from a volume ofblood including the thrombus to the heat transfer element. The resultanttemperature of the volume may be sufficient to substantially reduce thesize of a thrombus. For example, the resultant temperature of the volumemay be sufficiently high to substantially enhance plasminogen activationnear the thrombus.

Implementations of the invention may include one or more of thefollowing. The temperature of the blood may be adjusted by the heattransfer element to a temperature of between about 30° C. and 32° C. Thetemperature sufficient to substantially reduce the size of a thrombus isalso sufficient to substantially reduce plasmin inhibitor activity nearthe thrombus. The temperature of the heat transfer element may be raisedfrom a temperature sufficient to substantially reduce the size of thethrombus to a temperature sufficient to substantially rewarm the volume,and may further be cycled between these temperatures. In this case, thetemperature sufficient to reduce the size of the thrombus is betweenabout 25° C. and 32° C., and the temperature sufficient to substantiallyrewarm the volume is between about 34° C. and 36° C.

The delivering and adjusting may further include inserting the heattransfer element into the vessel and cooling the heat transfer elementby delivering a working fluid to the heat transfer element. The workingfluid may be delivered at a temperature of between about −3° C. and 1°C. The heat transfer element may be inflated with the working fluid,which may be delivered at a pressure of less than 5 atmospheres, such asabout 1 to 5 atmospheres.

Turbulence may also be induced in the flowing blood or in the workingfluid. Regarding the former, turbulence may be induced with a turbulenceintensity of greater than about 0.05. Blood turbulence may be induced ingreater than 20% of the period of the cardiac cycle within the carotidartery, such as during the entire period of the cardiac cycle. To induceturbulence in the working fluid, the inflating may include passing theworking fluid through a substantially helical-shaped structure. About 75to 200 watts of heat may be removed from the blood.

In another aspect, the invention relates to a method for dissolving ablood clot. The method includes introducing a catheter having a coolingelement into a blood vessel in which a blood clot has formed anddisposing the cooling element within the blood vessel such that bloodflows past the cooling element to the blood clot. At least a portion ofthe volume of blood surrounding the blood clot is cooled. Free streamturbulence may be induced in blood flowing over the catheter. The methodthus reduces inhibition of anti-clotting enzymes by the cooling.

In yet another aspect, the invention relates to a method of altering theactivity of an enzyme present in a flow of blood relative to theactivity of the enzyme at a normal blood temperature. The methodincludes delivering a heat transfer element to the blood flow upstreamof the enzyme, adjusting the temperature of the heat transfer elementsuch that the temperature of the heat transfer element is sufficient toalter the temperature of a local portion of the blood flow including theenzyme, and transferring heat between the portion of the blood flow andthe heat transfer element. The resultant temperature of the portion ofthe blood flow is sufficient to substantially alter the enzyme activitywithin at least the portion of the blood flow. Implementations of theinvention may include extending the technique to stationary volumes ofblood or tissue. The adjusting may further include cooling the heattransfer element by delivering a working fluid to the heat transferelement and inducing turbulence within the working fluid or in the flowof blood.

In a further aspect, the invention is related to a method for providingan optimal working temperature for a temperature-specific enzyme with adrug in a blood vessel. The method includes delivering a heat transferelement to a blood vessel, the blood vessel containing atemperature-specific enzyme. The temperature of the heat transferelement is adjusted such that the temperature-specific enzyme is heatedto a prespecified temperature range within at least a portion of whichthe optimal working temperature for a temperature-specific enzyme isattained. The optimal working temperature in the blood vessel issubstantially different from the normal body temperature in the bloodvessel.

In another aspect, the invention is directed towards a method forselective thrombolysis by selective vessel hypothermia The methodincludes introducing a catheter having a heat transfer element into ablood vessel in fluid communication with a thrombosed blood vessel. Theheat transfer element is cooled by flowing a working fluid through theheat transfer element. The blood is cooled by flowing the blood past theheat transfer element and inducing free stream turbulence in the blood,such that the blood is cooled to a prespecified temperature range. Athrombolytic drug is then delivered to the blood, the thrombolytic drughaving a working temperature within the prespecified temperature range.Implementations of the invention may include one or more of thefollowing. The drug may be chosen from tPA, urokinase, streptokinase,precursors of urokinase, and combinations thereof. If the drug is tPA,the prespecified temperature range may be between about 30° C. to 32° C.The blood may then be rewarmed and cycled. If the thrombolytic drug isstreptokinase, the prespecified temperature range may between about 30°C. and 32° C., and the rewarming may raise the blood temperature toabout 37° C. If the thrombolytic drug is urokinase, the prespecifiedtemperature range may be below about 28° C., and the rewarming may raisethe blood temperature to about 37° C. If the thrombolytic drug is aprecursor to urokinase, the prespecified temperature range may be belowabout 28° C., and the rewanning may raise the blood temperature to about37° C.

In yet another aspect, the blood may be warmed instead of cooled. Inthis case, if the drug is tPA, the prespecified temperature range may bebetween about 37° C. to 40° C.

In yet a further aspect, the invention is directed towards a method ofreducing certain deleterious and systemic effects of thrombolytic drugswhile allowing thrombolysis to effectively proceed via selective vesselhypothermia. The method includes introducing a catheter having a heattransfer element into a thrombosed blood vessel or into a blood vesselin fluid communication with a thrombosed blood vessel. The temperatureof the blood flowing through the blood vessel, prior to introduction ofthe heat transfer element, and averaged over the body, is at a firsttemperature or is alternatively within a first temperature range. Theheat transfer element is cooled by flowing a working fluid through theheat transfer element. The blood is cooled by flowing the blood past thecooled heat transfer element and by inducing free stream turbulence inthe blood, such that the blood is cooled to a prespecified temperaturerange. The presence of the free stream turbulence significantly enhancesthe heat transfer rate. A drug is then delivered to the blood. The drughas a working temperature within the prespecified temperature range. Thedrug is substantially less active at the first temperature or within thefirst temperature range. Alternatively, the drug has substantially lessactivity at the first temperature or within the first temperature range.Alternatively, the drug does not have a working temperature at the firsttemperature or within the first temperature range. The drug may be,e.g., a thrombolytic drug.

Advantages of the invention include one or more of the following. Clotlysis may be achieved conveniently and selectively, and may be inducedwithout the need for additional anticoagulants. The effects of ischemiaare reduced during the procedure, reducing damage to affected cells. Inthe case where drugs are administered to further treat a thrombus,hypothermia may also be induced as a complementary therapy to reduce theeffects of ischemia and to provide neural protection. In a case wheretemperature isoforms of known drugs or enzymes are used to provide atherapy, the drug action may be localized to a prespecified situs byselective cooling. In other words, the drug only works at a particulartemperature, and the particular temperature is only achieved at theworking situs. In this way, procedures such as thrombolysis may beachieved without adverse systemic effects.

The novel features of this invention, as well as the invention itself,will be best understood from the attached drawings, taken along with thefollowing description, in which similar reference characters refer tosimilar parts, and in which:

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is an elevation view of a turbulence inducing heat transferelement within an artery;

FIG. 2 is an elevation view of one embodiment of a heat transfer elementwhich may be employed according to the invention;

FIG. 3 is longitudinal section view of the heat transfer element of FIG.2;

FIG. 4 is a transverse section view of the heat transfer element of FIG.2;

FIG. 5 is a perspective view of the heat transfer element of FIG. 2 inuse within a blood vessel;

FIG. 6 is a cut-away perspective view of an alternative embodiment of aheat transfer element which may be employed according to the invention;

FIG. 7 is a transverse section view of the heat transfer element of FIG.6; and

FIG. 8 is a schematic representation of the invention being used in oneembodiment to cool the brain of a patient.

DETAILED DESCRIPTION OF THE INVENTION

The temperature of a selected organ may be intravascularly regulated bya heat transfer element placed in the organ's feeding artery to absorbor deliver heat to or from the blood flowing into the organ. While themethod is described with respect to blood flow into an organ, it isunderstood that heat transfer within a volume of tissue is analogous. Inthe latter case, heat transfer is predominantly by conduction.

The heat transfer may cause either a cooling or a heating of theselected organ. A heat transfer element that selectively alters thetemperature of an organ should be capable of providing the necessaryheat transfer rate to produce the desired cooling or heating effectwithin the organ to achieve a desired temperature.

The heat transfer element should be small and flexible enough to fitwithin the feeding artery while still allowing a sufficient blood flowto reach the organ in order to avoid ischemic organ damage. Feedingarteries, like the carotid artery, branch off the aorta at variouslevels. Subsidiary arteries continue to branch off these initialbranches. For example, the internal carotid artery branches off thecommon carotid artery near the angle of the jaw. The heat transferelement is typically inserted into a peripheral artery, such as thefemoral artery, using a guide catheter or guide wire, and accesses afeeding artery by initially passing though a series of one or more ofthese branches. Thus, the flexibility and size, e.g., the diameter, ofthe heat transfer element are important characteristics. Thisflexibility is achieved as is described in more detail below.

These points are illustrated using brain cooling as an example. Thecommon carotid artery supplies blood to the head and brain. The internalcarotid artery branches off the common carotid artery to supply blood tothe anterior cerebrum. The heat transfer element may be placed into thecommon carotid artery or into both the common carotid artery and theinternal carotid artery.

The benefits of hypothermia described above are achieved when thetemperature of the blood flowing to the brain is reduced to between 30°C. and 32° C. A typical brain has a blood flow rate through each carotidartery (right and left) of approximately 250-375 cubic centimeters perminute (cc/min). With this flow rate, calculations show that the heattransfer element should absorb approximately 75-175 watts of heat whenplaced in one of the carotid arteries to induce the desired coolingeffect. Smaller organs may have less blood flow in their respectivesupply arteries and may require less heat transfer, such as about 25watts.

The method employs conductive and convective heat transfers. Once thematerials for the device and a working fluid are chosen, the conductiveheat transfers are solely dependent on the temperature gradients.Convective heat transfers, by contrast, also rely on the movement offluid to transfer heat Forced convection results when the heat transfersurface is in contact with a fluid whose motion is induced (or forced)by a pressure gradient, area variation, or other such force. In the caseof arterial flow, the beating heart provides an oscillatory pressuregradient to force the motion of the blood in contact with the heattransfer surface. One of the aspects of the device uses turbulence toenhance this forced convective heat transfer.

The rate of convective heat transfer Q is proportional to the product ofS, the area of the heat transfer element in direct contact with thefluid, ΔT=T_(b)−T_(s), the temperature differential between the surfacetemperature T_(s) of the heat transfer element and the free stream bloodtemperature T_(b), and {overscore (h_(c)+L )}, the average convectionheat transfer coefficient over the heat transfer area. {overscore(h_(c)+L )} is sometimes called the “surface coefficient of heattransfer” or the “convection heat transfer coefficient”.

The magnitude of the heat transfer rate Q to or from the fluid flow canbe increased through manipulation of the above three parameters.Practical constraints limit the value of these parameters and how muchthey can be manipulated. For example, the internal diameter of thecommon carotid artery ranges from 6 to 8 mm. Thus, the heat transferelement residing therein may not be much larger than 4 mm in diameter toavoid occluding the vessel. The length of the heat transfer elementshould also be limited. For placement within the internal and commoncarotid artery, the length of the heat transfer element is limited toabout 10 cm. This estimate is based on the length of the common carotidartery, which ranges from 8 to 12 cm.

Consequently, the value of the surface area S is limited by the physicalconstraints imposed by the size of the artery into which the device isplaced. Surface features, such as fins, can be used to increase thesurface area of the heat transfer element, however, these features alonecannot provide enough surface area enhancement to meet the required heattransfer rate to effectively cool the brain.

One may also attempt to vary the magnitude of the heat transfer rate byvarying ΔT. The value of ΔT=T_(b)−T_(s) can be varied by varying thesurface temperature T_(s) of the heat transfer element. The allowablesurface temperature of the heat transfer element is limited by thecharacteristics of blood. The blood temperature is fixed at about 37°C., and blood freezes at approximately 0° C. When the blood approachesfreezing, ice emboli may form in the blood which may lodge downstream,causing serious ischemic injury.

Furthermore, reducing the temperature of the blood also increases itsviscosity which results in a small decrease in the value of {overscore(h_(c)+L )}. Increased viscosity of the blood may further result in anincrease in the pressure drop within the artery, thus compromising theflow of blood to the brain. Given the above constraints, it isadvantageous to limit the surface temperature of the heat transferelement to approximately 1° C.-5° C., thus resulting in a maximumtemperature differential between the blood stream and the heat transferelement of approximately 32° C.-36° C.

One may also attempt to vary the magnitude of the heat transfer rate byvarying {overscore (h_(c)+L )}. Fewer constraints are imposed on thevalue of the convection heat transfer coefficient h . The mechanisms bywhich the value of {overscore (h_(c)+L )} may be increased are complex.However, one way to increase {overscore (h_(c)+L )} for a fixed meanvalue of the velocity is to increase the level of turbulent kineticenergy in the fluid flow.

The heat transfer rate Q_(no-flow) in the absence of fluid flow isproportional to ΔT, the temperature differential between the surfacetemperature T_(s) of the heat transfer element and the free stream bloodtemperature T_(b) times k, the diffusion constant, and is inverselyproportion to δ, the thickness of the boundary layer.

The magnitude of the enhancement in heat transfer by fluid flow can beestimated by taking the ratio of the heat transfer rate with fluid flowto the heat transfer rate in the absence of fluid flowN=Q_(flow)/Q_(no-flow)={overscore (h_(c)+L )}/(k/δ). This ratio iscalled the Nusselt number (“Nu”). For convective heat transfer betweenblood and the surface of the heat transfer element, Nusselt numbers of30-80 have been found to be appropriate for selective coolingapplications of various organs in the human body. Nusselt numbers aregenerally dependent on several other numbers: the Reynolds number, theWomersley number, and the Prandtl number.

Stirring-type mechanisms, which abruptly change the direction ofvelocity vectors, may be utilized to induce turbulent kinetic energy andincrease the heat transfer rate. The level of turbulence so created ischaracterized by the turbulence intensity . Turbulence intensity isdefined as the root mean square of the fluctuating velocity divided bythe mean velocity. Such mechanisms can create high levels of turbulenceintensity in the free stream, thereby increasing the heat transfer rate.This turbulence intensity should ideally be sustained for a significantportion of the cardiac cycle, and should ideally be created throughoutthe free stream and not just in the boundary layer.

Turbulence does occur for a short period in the cardiac cycle anyway. Inparticular, the blood flow is turbulent during a small portion of thedescending systolic flow. This portion is less than 20% of the period ofthe cardiac cycle. If a heat transfer element is placed co-axiallyinside the artery, the heat transfer rate will be enhanced during thisshort interval. For typical of these fluctuations, the turbulenceintensity is at least 0.05. In other words, the instantaneous velocityfluctuations deviate from the mean velocity by at least 5%. Althoughideally turbulence is created throughout the entire period of thecardiac cycle, the benefits of turbulence are obtained if the turbulenceis sustained for 75%, 50% or even as low as 30% or 20% of the cardiaccycle.

One type of turbulence-inducing heat transfer element which may beadvantageously employed to provide heating or cooling of an organ orvolume is described in co-pending U.S. patent application Ser. No.09/103,342 to Dobak and Lasheras for a “Selective Organ Cooling Catheterand Method of Using the Same,” incorporated by reference above. In thatapplication, and as described below, the heat transfer element is madeof a high thermal conductivity material, such as metal. The use of ahighly thermally conductive material increases the heat transfer ratefor a given temperature differential between the coolant within the heattransfer element and the blood. This facilitates the use of a highertemperature coolant within the heat transfer element, allowing safercoolants, such as water, to be used. Highly thermally conductivematerials, such as metals, tend to be rigid. In that application,bellows provided a high degree of articulation that compensated for theintrinsic stiffness of the metal. The device size was minimized, e.g.,less than 4 mm, to prevent blockage of the blood flowing in the artery.Therefore, the design of the heat transfer element should facilitateflexibility in an inherently inflexible material.

To create the desired level of turbulence intensity in the blood freestream during the whole cardiac cycle, one embodiment of the device usesa modular design. This design creates helical blood flow and produces ahigh level of turbulence in the free stream by periodically forcingabrupt changes in the direction of the helical blood flow. FIG. 1 is aperspective view of such a turbulence inducing heat transfer elementwithin an artery. Turbulent flow would be found at point 114, in thefree stream area. The abrupt changes in flow direction are achievedthrough the use of a series of two or more heat transfer segments, eachcomprised of one or more helical ridges. To affect the free stream, thedepth of the helical ridge is larger than the thickness of the boundarylayer which would develop if the heat transfer element had a smoothcylindrical surface.

The use of periodic abrupt changes in the helical direction of the bloodflow in order to induce strong free stream turbulence may be illustratedwith reference to a common clothes washing machine. The rotor of awashing machine spins initially in one direction causing laminar flow.When the rotor abruptly reverses direction, significant turbulentkinetic energy is created within the entire wash basin as the changingcurrents cause random turbulent motion within the clothes-water slurry.

FIG. 2 is an elevation view of one embodiment of a heat transfer element14. The heat transfer element 14 is comprised of a series of elongated,articulated segments or modules 20, 22, 24. Three such segments areshown in this embodiment, but two or more such segments could be used.As seen in FIG. 2, a first elongated heat transfer segment 20 is locatedat the proximal end of the heat transfer element 14. Aturbulence-inducing exterior surface of the segment 20 comprises fourparallel helical ridges 28 with four parallel helical grooves 26therebetween. One, two, three, or more parallel helical ridges 28 couldalso be used. In this embodiment, the helical ridges 28 and the helicalgrooves 26 of the heat transfer segment 20 have a left hand twist,referred to herein as a counter-clockwise spiral or helical rotation, asthey proceed toward the distal end of the heat transfer segment 20.

The first heat transfer segment 20 is coupled to a second elongated heattransfer segment 22 by a first bellows section 25, which providesflexibility and compressibility. The second heat transfer segment 22comprises one or more helical ridges 32 with one or more helical grooves30 therebetween. The ridges 32 and grooves 30 have a right hand, orclockwise, twist as they proceed toward the distal end of the heattransfer segment 22. The second heat transfer segment 22 is coupled to athird elongated heat transfer segment 24 by a second bellows section 27.The third heat transfer segment 24 comprises one or more helical ridges36 with one or more helical grooves 34 therebetween. The helical ridge36 and the helical groove 34 have a left hand, or counter-clockwise,twist as they proceed toward the distal end of the heat transfer segment24. Thus, successive heat transfer segments 20, 22, 24 of the heattransfer element 14 alternate between having clockwise andcounterclockwise helical twists. The actual left or right hand twist ofany particular segment is immaterial, as long as adjacent segments haveopposite helical twist.

In addition, the rounded contours of the ridges 28, 32, 36 also allowthe heat transfer element 14 to maintain a relatively atraumaticprofile, thereby minimizing the possibility of damage to the bloodvessel wall. A heat transfer element may be comprised of two, three, ormore heat transfer segments.

The bellows sections 25, 27 are formed from seamless and nonporousmaterials, such as metal, and therefore are impermeable to gas, whichcan be particularly important, depending on the type of working fluidwhich is cycled through the heat transfer element 14. The structure ofthe bellows sections 25, 27 allows them to bend, extend and compress,which increases the flexibility of the heat transfer element 14 so thatit is more readily able to navigate through blood vessels. The bellowssections 25, 27 also provide for axial compression of the heat transferelement 14, which can limit the trauma when the distal end of the heattransfer element 14 abuts a blood vessel wall. The bellows sections 25,27 are also able to tolerate cryogenic temperatures without a loss ofperformance.

The exterior surfaces of the heat transfer element 14 can be made frommetal, and may comprise very high thermal conductivity materials such asnickel, thereby facilitating heat transfer. Alternatively, other metalssuch as stainless steel, titanium, aluminum, silver, copper and thelike, can be used, with or without an appropriate coating or treatmentto enhance biocompatibility or inhibit clot formation. Suitablebiocompatible coatings include, e.g., gold, platinum or polymerparalyene. The heat transfer element 14 may be manufactured by plating athin layer of metal on a mandrel that has the appropriate pattern. Inthis way, the heat transfer element 14 may be manufactured inexpensivelyin large quantities, which is an important feature in a disposablemedical device.

Because the heat transfer element 14 may dwell within the blood vesselfor extended periods of time, such as 24-48 hours or even longer, it maybe desirable to treat the surfaces of the heat transfer element 14 toavoid clot formation. In particular, one may wish to treat the bellowssections 25, 27 because stagnation of the blood flow may occur in theconvolutions, thus allowing clots to form and cling to the surface toform a thrombus. One means by which to prevent thrombus formation is tobind an antithrombogenic agent to the surface of the heat transferelement 14. For example, heparin is known to inhibit clot formation andis also known to be useful as a biocoating. Alternatively, the surfacesof the heat transfer element 14 may be bombarded with ions such asnitrogen. Bombardment with nitrogen can harden and smooth the surfaceand, thus prevent adherence of clotting factors to the surface.

FIG. 3 is a longitudinal sectional view of the heat transfer element 14,taken along line 3—3 in FIG. 2. Some interior contours are omitted forpurposes of clarity. An inner tube 42 creates an inner coaxial lumen 42and an outer coaxial lumen 46 within the heat transfer element 14. Oncethe heat transfer element 14 is in place in the blood vessel, a workingfluid such as saline or other aqueous solution may be circulated throughthe heat transfer element 14. Fluid flows up a supply catheter into theinner coaxial lumen 40. At the distal end of the heat transfer element14, the working fluid exits the inner coaxial lumen 40 and enters theouter lumen 46. As the working fluid flows through the outer lumen 46,heat is transferred from the working fluid to the exterior surface 37 ofthe heat transfer element 14. Because the heat transfer element 14 isconstructed from a high conductivity material, the temperature of itsexterior surface 37 may reach very close to the temperature of theworking fluid. The tube 42 may be formed as an insulating divider tothermally separate the inner lumen 40 from the outer lumen 46. Forexample, insulation may be achieved by creating longitudinal airchannels in the wall of the insulating tube 42. Alternatively, theinsulating tube 42 may be constructed of a non-thermally conductivematerial like polytetrafluoroethylene or some other polymer.

It is important to note that the same mechanisms that govern the heattransfer rate between the exterior surface 37 of the heat transferelement 14 and the blood also govern the heat transfer rate between theworking fluid and the interior surface 38 of the heat transfer element14. The heat transfer characteristics of the interior surface 38 areparticularly important when using water, saline or other fluid whichremains a liquid as the coolant. Other coolants such as freon undergonucleate boiling and create turbulence through a different mechanism.Saline is a safe coolant because it is non-toxic, and leakage of salinedoes not result in a gas embolism, which could occur with the use ofboiling refrigerants. Since turbulence in the coolant is enhanced by theshape of the interior surface 38 of the heat transfer element 14, thecoolant can be delivered to the heat transfer element 14 at a warmertemperature and still achieve the necessary heat transfer rate.

This has a number of beneficial implications in the need for insulationalong the catheter shaft length. Due to the decreased need forinsulation, the catheter shaft diameter can be made smaller. Theenhanced heat transfer characteristics of the interior surface of theheat transfer element 14 also allow the working fluid to be delivered tothe heat transfer element 14 at lower flow rates and lower pressures.High pressures may make the heat transfer element stiff and cause it topush against the wall of the blood vessel, thereby shielding part of theexterior surface 37 of the heat transfer element 14 from the blood.Because of the increased heat transfer characteristics achieved by thealternating helical ridges 28, 32, 36, the pressure of the working fluidmay be as low as 5 atmospheres, 3 atmospheres, 2 atmospheres or evenless than 1 atmosphere.

FIG. 4 is a transverse sectional view of the heat transfer element 14,taken at a location denoted by the line 4—4 in FIG. 2. FIG. 4illustrates a five-lobed embodiment, whereas FIG. 2 illustrates afour-lobed embodiment. As mentioned earlier, any number of lobes mightbe used. In FIG. 4, the coaxial construction of the beat transferelement 14 is clearly shown. The inner coaxial lumen 40 is defined bythe insulating coaxial tube 42. The outer lumen 46 is defined by theexterior surface of the insulating coaxial tube 42 and the interiorsurface 38 of the heat transfer element 14. In addition, the helicalridges 32 and helical grooves 30 may be seen in FIG. 4. As noted above,in the preferred embodiment, the depth of the grooves, d_(i), is greaterthan the boundary layer thickness which would have developed if acylindrical heat transfer element were introduced. For example, in aheat transfer element 14 with a 4 mm outer diameter, the depth of theinvaginations, d_(i), may be approximately equal to 1 mm if designed foruse in the carotid artery. Although FIG. 4 shows four ridges and fourgrooves, the number of ridges and grooves may vary. Thus, heat transferelements with 1, 2, 3, 4, 5, 6, 7, 8 or more ridges are specificallycontemplated.

FIG. 5 is a perspective view of a heat transfer element 14 in use withina blood vessel, showing only one helical lobe per segment for purposesof clarity. Beginning from the proximal end of the heat transfer element(not shown in FIG. 5), as the blood moves forward during the systolicpulse, the first helical heat transfer segment 20 induces acounter-clockwise rotational inertia to the blood. As the blood reachesthe second segment 22, the rotational direction of the inertia isreversed, causing turbulence within the blood. Further, as the bloodreaches the third segment 24, the rotational direction of the inertia isagain reversed. The sudden changes in flow direction actively reorientand randomize the velocity vectors, thus ensuring turbulence throughoutthe bloodstream. During turbulent flow, the velocity vectors of theblood become more random and, in some cases, become perpendicular to theaxis of the artery. In addition, as the velocity of the blood within theartery decreases and reverses direction during the cardiac cycle,additional turbulence is induced and turbulent motion is sustainedthroughout the duration of each pulse through the same mechanismsdescribed above.

Thus, a large portion of the volume of warm blood in the vessel isactively brought in contact with the heat transfer element 14, where itcan be cooled by direct contact rather than being cooled largely byconduction through adjacent laminar layers of blood. As noted above, thedepth of the grooves 26, 30, 34 (FIG. 2) is greater than the depth ofthe boundary layer which would develop if a straight-walled heattransfer element were introduced into the blood stream. In this way,free stream turbulence is induced. In the preferred embodiment, in orderto create the desired level of turbulence in the entire blood streamduring the whole cardiac cycle, the heat transfer element 14 creates aturbulence intensity greater than about 0.05. The turbulence intensitymay be greater than 0.05, 0.06, 0.07 or up to 0.10 or 0.20 or greater.

Referring back to FIG. 2, the heat transfer element 14 has been designedto address all of the design criteria discussed above. First, the heattransfer element 14 is flexible and is made of a highly conductivematerial. The flexibility is provided by a segmental distribution ofbellows sections 25, 27 which provide an articulating mechanism. Bellowshave a known convoluted design which provides flexibility. Second, theexterior surface area 37 has been increased through the use of helicalridges 28, 32, 36 and helical grooves 26, 30, 34. The ridges also allowthe heat transfer element 14 to maintain a relatively atraumaticprofile, thereby minimizing the possibility of damage to the vesselwall. Third, the heat transfer element 14 has been designed to promoteturbulent kinetic energy both internally and externally. The modular orsegmental design allows the direction of the invaginations to bereversed between segments. The alternating helical rotations create analternating flow that results in mixing the blood in a manner analogousto the mixing action created by the rotor of a washing machine thatswitches directions back and forth. This mixing action is intended topromote high level turbulent kinetic energy to enhance the heat transferrate. The alternating helical design also causes beneficial mixing, orturbulent kinetic energy, of the working fluid flowing internally.

FIG. 6 is a cut-away perspective view of an alternative embodiment of aheat transfer element 50. An external surface 52 of the heat transferelement 50 is covered with a series of axially staggered protrusions 54.The staggered nature of the outer protrusions 54 is readily seen withreference to FIG. 7 which is a transverse crosssectional view taken at alocation denoted by the line 7—7 in FIG. 6. In order to induce freestream turbulence, the height, d_(p), of the staggered outer protrusions54 is greater than the thickness of the boundary layer which woulddevelop if a smooth heat transfer element had been introduced into theblood stream. As the blood flows along the external surface 52, itcollides with one of the staggered protrusions 54 and a turbulent wakeflow is created behind the protrusion. As the blood divides and swirlsalong side of the first staggered protrusion 54, its turbulent wakeencounters another staggered protrusion 54 within its path preventingthe re-lamination of the flow and creating yet more turbulence. In thisway, the velocity vectors are randomized and turbulence is created notonly in the boundary layer but throughout the free stream. As is thecase with the preferred embodiment, this geometry also induces aturbulent effect on the internal coolant flow.

A working fluid is circulated up through an inner coaxial lumen 56defined by an insulating coaxial tube 58 to a distal tip of the heattransfer element 50. The working fluid then traverses an outer coaxiallumen 60 in order to transfer heat to the exterior surface 52 of theheat transfer element 50. The inside surface of the heat transferelement 50 is similar to the exterior surface 52, in order to induceturbulent flow of the working fluid. The inner protrusions can bealigned with the outer protrusions 54, as shown in FIG. 7, or they canbe offset from the outer protrusions 54, as shown in FIG. 6.

FIG. 8 is a schematic representation of the invention being used to coolthe brain of a patient. The selective organ hypothermia apparatus shownin FIG. 8 includes a working fluid supply 10, preferably supplying achilled liquid such as water, alcohol or a halogenated hydrocarbon, asupply catheter 12 and the heat transfer element 14. The supply catheter12 has a coaxial construction. An inner coaxial lumen within the supplycatheter 12 receives coolant from the working fluid supply 10. Thecoolant travels the length of the supply catheter 12 to the heattransfer element 14 which serves as the cooling tip of the catheter. Atthe distal end of the heat transfer element 14, the coolant exits theinsulated interior lumen and traverses the length of the heat transferelement 14 in order to decrease the temperature of the heat transferelement 14. The coolant then traverses an outer lumen of the supplycatheter 12 so that it may be disposed of or recirculated. The supplycatheter 12 is a flexible catheter having a diameter sufficiently smallto allow its distal end to be inserted percutaneously into an accessibleartery such as the femoral artery of a patient as shown in FIG. 8. Thesupply catheter 12 is sufficiently long to allow the heat transferelement 14 at the distal end of the supply catheter 12 to be passedthrough the vascular system of the patient and placed in the internalcarotid artery or other small artery. The method of inserting thecatheter into the patient and routing the heat transfer element 14 intoa selected artery is well known in the art.

Although the working fluid supply 10 is shown as an exemplary coolingdevice, other devices and working fluids may be used. For example, inorder to provide cooling, freon, perflourocarbon, water, or saline maybe used, as well as other such coolants.

The heat transfer element can absorb or provide over 75 Watts of heat tothe blood stream and may absorb or provide as much as 100 Watts, 150Watts, 170 Watts or more. For example, a heat transfer element with adiameter of 4 mm and a length of approximately 10 cm using ordinarysaline solution chilled so that the surface temperature of the heattransfer element is approximately 5° C. and pressurized at 2 atmospherescan absorb about 100 Watts of energy from the bloodstream. Smallergeometry heat transfer elements may be developed for use with smallerorgans which provide 60 Watts, 50 Watts, 25 Watts or less of heattransfer.

The practice of the present invention is illustrated in the followingnon-limiting example.

Exemplary Procedure

1. The patient is initially assessed, resuscitated, and stabilized.

2. The procedure is carried out in an angiography suite or surgicalsuite equipped with flouroscopy.

3. Because the catheter is placed into the common carotid artery, it isimportant to determine the presence of stenotic atheromatous lesions. Acarotid duplex (doppler/ultrasound) scan can quickly and non-invasivelymake this determinations. The ideal location for placement of thecatheter is in the left carotid so this may be scanned first. If diseaseis present, then the right carotid artery can be assessed. This test canbe used to detect the presence of proximal common carotid lesions byobserving the slope of the systolic upstroke and the shape of thepulsation. Although these lesions are rare, they could inhibit theplacement of the catheter. Examination of the peak blood flow velocitiesin the internal carotid can determine the presence of internal carotidartery lesions. Although the catheter is placed proximally to suchlesions, the catheter may exacerbate the compromised blood flow createdby these lesions. Peak systolic velocities greater that 130 cm/sec andpeak diastolic velocities greater than about 100 cm/sec in the internalindicate the presence of at least 70% stenosis. Stenosis of 70% or moremay warrant the placement of a stent to open up the internal arterydiameter.

4. The ultrasound can also be used to determine the vessel diameter andthe blood flow and the catheter with the appropriately sized heattransfer element could be selected.

5. After assessment of the arteries, the patients inguinal region issterilely prepped and infiltrated with lidocaine.

6. The femoral artery is cannulated and a guide wire may be inserted tothe desired carotid artery. Placement of the guide wire is confirmedwith flouroscopy.

7. An angiographic catheter can be fed over the wire and contrast mediainjected into the artery to further to assess the anatomy of thecarotid.

8. Alternatively, the femoral artery is cannulated and a 10-12.5 french(f) introducer sheath is placed.

9. A guide catheter is placed into the desired common carotid artery. Ifa guiding catheter is placed, it can be used to deliver contrast mediadirectly to further assess carotid anatomy.

10. A 10 f −12 f (3.3-4.0 mm) (approximate) cooling catheter issubsequently filled with saline and all air bubbles are removed.

11. The cooling catheter is placed into the carotid artery via theguiding catheter or over the guidewire. Placement is confirmed withflouroscopy.

12. Alternatively, the cooling catheter tip is shaped (angled or curvedapproximately 45 degrees), and the cooling catheter shaft has sufficientpushability and torqueability to be placed in the carotid without theaid of a guide wire or guide catheter.

13. The cooling catheter is connected to a pump circuit also filled withsaline and free from air bubbles. The pump circuit has a heat exchangesection that is immersed into a water bath and tubing that is connectedto a peristaltic pump. The water bath is chilled to approximately 0° C.

14. Cooling is initiated by starting the pump mechanism. The salinewithin the cooling catheter is circulated at 5 cc/sec. The salinetravels through the heat exchanger in the chilled water bath and iscooled to approximately 1° C.

15. It subsequently enters the cooling catheter where it is delivered tothe heat transfer element. The saline is warmed to approximately 5-7° C.as it travels along the inner lumen of the catheter shaft to the end ofthe heat transfer element.

16. The saline then flows back through the heat transfer element incontact with the inner metallic surface. The saline is further warmed inthe heat transfer element to 12-15° C., and in the process, heat isabsorbed from the blood, cooling the blood to 30° C. to 32° C.

17. The chilled blood then goes on to chill the brain. It is estimatedthat 15-30 minutes will be required to cool the brain to 30 to 32° C.

18. The warmed saline travels back down the outer lumen of the cathetershaft and back to the chilled water bath where it is cooled to 1° C.

19. The pressure drops along the length of the circuit are estimated tobe 2-3 atmospheres.

20. The cooling can be adjusted by increasing or decreasing the flowrate of the saline. Monitoring of the temperature drop of the salinealong the heat transfer element will allow the flow to be adjusted tomaintain the desired cooling effect.

21. The catheter is left in place to provide cooling for 12 to 24 hours.

22. If desired, warm saline can be circulated to promote warming of thebrain at the end of the therapeutic cooling period.

The above devices and techniques, including those disclosed in theapplications incorporated by reference above, provide effective coolingor heating of a fluid such as blood. The heating or cooling may occureither in the affected vessel or in a vessel in fluid communication withthe affected vessel. In this disclosure, “fluid communication” betweentwo vessels refers to a situation where one vessel either feeds or isfed by the other. One application of these devices and techniques is forclot lysis. However, other types of enzyme activations may also beadvantageously induced. The method disclosed below is applicable toother devices and techniques so long as they are also capable of heatingor cooling blood.

As noted above, enzymes have been delivered to patients in drug orintravenous form for clot lysing. These enzymes are in addition tonaturally occuring enzymes already in the blood plasma. The activity ofenzymes is at least partially adjusted by control of environmentaltemperature. A method according to an embodiment of the inventionselectively controls enzyme activity by controlling the temperature ofthe environment of the enzyme. This controlled enzyme activity allowsselective thrombolysis by selective vessel hypothermia in a mannerdescribed in more detail below.

Several experimental procedures have been reported on animals and clotpreparations at various temperatures, as disclosed below, andappropriate temperature regimes for thrombolysis may be inferred withsome accuracy. However, the mechanisms by which enzyme environmentaltemperature controls thrombolysis are not yet well characterized.Disclosed below are several suggested mechanisms. These suggestedmechanisms are conjecture, and should not be construed as limiting, inany way, the method of the invention.

The suggested mechanisms rely to a certain extent on the knownmechanisms for fibrinolysis. In particular, plasminogen is the inertprecursor of plasmin. Plasmin is an enzyme that lyses clots, i.e.,cleaves peptide bonds in fibrin. Plasminogen binds to fibrin and, whenactivated by an appropriate enzyme, such as tPA, UK, SK, etc., convertsto plasmin. Plasminogen may also be activated in solution. Inhibitorssuch as α₂-antiplasmin moderate plasmin activity by inactivating plasminreleased from a fibrin surface almost instantaneously. α₂-antiplasmincan even inactivate plasmin bound to a fibrin surface, but this processrequires about 10 seconds.

One suggested mechanism concerns the action of the inhibitors. Theactivity of α₂-antiplasmin is lessened at low temperatures and thus isless effective at inactivating plasmin. In this case, more plasmin isavailable to lyse clots and thus fibrinolysis is enhanced.

A related effect is due to the effect of plasmin levels on plasminogenlevels. Increased plasmin levels may lead to increased plasminogenlevels circulating in solution. Moreover, decreased activity ofα₂-antiplasmin also leads to increased plasminogen levels becauseα₂-antiplasmin binds plasminogen, and less α₂-antiplasmin means less ofsuch binding.

Increased plasminogen levels also suggests several other mechanisms forclot lysing.

For example, plasmin cleaves single-chain urokinase (“scu-PA” or“pro-UK”) to form UK, i.e., pro-UK is a precursor to UK. Pro-UK, liketPA, cannot efficiently activate plasminogen in solution, but it canreadily activate plasminogen bound to fibrin. Thus, increasedplasminogen, together with the body's own UK or tPA, or similar enzymesprovided intravenously, may result in more localized lysing of fibrin,e.g. directly at the clot situs.

Another suggested mechanism results from increased plasminogen. UK canactivate both plasminogen in solution and plasminogen bound to fibrin.Thus, increased plasminogen levels, together with the body's own UK, orthat provided intravenously, results in both localized lysing of fibrinand enhanced activation of plasminogen in solution.

Another suggested mechanism results from the conjectured bond of plasminto fibrin. Plasmin may stay bound to fibrin for a longer period in thehypothermic state. Thus, more time may be available to lyse clots,increasing overall fibrinolysis.

The hypothermic temperatures at which increased fibrinolysis occurs havenot been fully explored. However, it has been shown that clot sampleshave benefited from temperatures of, e.g., 25° C. or below. For humanpatients, it is believed that temperatures of 30° C. to 32° C. may wellbe appropriate and advantageously employed in the method of theinvention.

In a related embodiment of the invention, the method may further employa step of rewarming the cooled organ from the low temperature of, e.g.30° C. The temperature range for rewarming may be from about 20° C. to37° C. depending on the patient, the condition, the hypothermictemperature, and so on. Rewarming has been shown to have a beneficialeffect in certain studies, perhaps by increasing the rate at which clotlysis occurs. In another related embodiment of the invention, the methodmay further employ temperature cycling the blood in the vessel from ahypothermic temperature to a rewarmed temperature. In this way, therewarming temperature regime is achieved repeatedly and thus so is theenhanced fibrinolysis.

EXAMPLE ONE

(Non-Drug)

Researchers have studied the effect of temperature on fibrinolysis inthe context of drug studies. As part of these studies, control groupsare investigated in which no drugs are introduced. In one suchinvestigation using clot samples, clot lysis was investigated whilevarying clot temperatures in a range of 25° C. to 41° C. In the absenceof drugs, enhanced clot lysis was seen at the lower part of thetemperature range. It is believed that this study can be extended tohumans, and thus fibrinolytic activity can be enhanced at lowertemperatures.

EXAMPLE TWO

(Non-Drug)

In another non-drug study of the effect of temperature on fibrinolysis,clot lysis in dogs was investigated while varying clot temperatures in arange of 20° C. to 36° C. The dog's temperature was lowered from anormal temperature to a low temperature. A gradual rewarming periodfollowed the low temperature period.

Enhanced clot lysis was observed at lower temperatures as compared tohigher temperatures. In particular, the maximum fibrinolytic activityoccurred in the early rewarming period, ie., from 20° C. to about 25° C.It is believed that this study can be extended to humans, and thatfibrinolytic activity can be enhanced at lower temperatures, especiallyduring periods of rewarming.

An advantage of all of these embodiments of the method is that clotlysis can be achieved in a simple manner and without the need for drugs.An additional advantage results from the reduced temperature of theblood which helps to protect the cells from ischemia at the same timelysis is occurring. Thus, clot lysis and cooling occur simultaneously,providing an effective and aggressive dual therapy. When dual therapiesare employed, cooling catheters may be inserted in both femoral arteriesfor transit to the brain. One cooling catheter cools the brain, whilethe other cools the blood in the artery leading to the clot. The latterprovides the beneficial effects noted above.

In some cases, of course, the nature or extent of the clot is such thatlysing may only occur with drug intervention. In these cases,thrombolytic drugs, such as those disclosed above, may be introduced toinduce the fibrinolysis.

These drugs are effective at treating the thrombus. However, it may alsobe advantageous to cool the brain as a separate neuroprotective measure.The effectiveness of both therapies is enhanced when applied as soon aspossible. Thus, it is often desirable to apply both therapiessimultaneously. In this way, hypothermia is induced as a neuroprotectivemeasure, and may further induce clot lysing per se in the mannerdescribed above.

A difficulty with this approach is that the techniques areinterdependent. Drugs depend on enzymes for their activity, and enzymesare temperature-dependent. In fact, past studies have demonstrated thatthe enzyme activity of these specific thrombolytic drugs on clot samplesis temperature-dependent. In other words, their effect on clot orthrombus lysis varies over a temperature range. For typicaltemperature-specific enzymes, the greatest activity occurs at an optimaltemperature. The optimal temperature may be about 37° C. in the case ofknown thrombolytics, as this is the normal human body temperature.

Enzyme activity drastically reduces above certain temperatures as theenzyme denatures and becomes inactive. At the opposite extreme, enzymeactivity reduces below certain temperatures as the enzyme lacks theenergy necessary to couple to a substrate. Therefore, when the brain orother tissue is at a temperature different from normal body temperature,e.g., during hypothermia, an isoform of the enzyme is preferably usedwhich has an optimal working temperature at the hypothermic bodytemperature. In this disclosure, such an isoform which is effective at adifferent temperature is said to have a “working temperature” at thedifferent temperature or within a range of different temperatures.

In this disclosure, the term “isoform” of an enzyme is used as follows.If a first enzyme catalyzes a reaction at a first temperature, and adifferent enzyme catalyzes the same reaction at a second temperature,then the different enzyme is an “isoform” of the first enzyme within themeaning intended here.

For patients undergoing hypothermia, the physician may preferably use alow-temperature isoform; for patients whose temperatures have beenraised, the physician may preferably use a high-temperature isoform. Theform of the enzyme will preferably have an optimal activity curve at ornear the desired temperature. Known enzymes are described below,followed by a methodology for choosing enzymes which are not yet known.

EXAMPLE THREE

(SK)

Researchers have investigated the effect of temperature on thefibrinolytic activity of an SK mixture. In one such effort, clots weretreated with a mixture of plasminogen (2 mg) and SK (100 IU) in a totalvolume of 15 ml PBS. The temperature of the clots was raised from 24° C.to 37° C. These researchers found that heating enhanced the fibrinolyticactivity. In other words, heating from a hypothermic temperature tonormal body temperature increased clot lysing for clots treated with SK.

It is believed that such general trends may be extended to patientswithout lack of accuracy. Patients may be provided with a drug such asstreptokinase and may undergo hypothermia using, e.g., one of thedevices or methods described above. In particular, a cooling cathetermay be placed in an artery supplying blood to a thrombosed vessel. Thecatheter may include a separate lumen through which the SK mixture maybe delivered. A coolant or working fluid may be supplied to the coolingcatheter, causing the same to cool and to cool the blood adjacent a heattransfer element located at a distal tip of the cooling catheter. Thiscooling step may include the step of inducing turbulence in the bloodflowing through the vessel and/or in the working fluid. SK may bedelivered through the separate drug delivery lumen. The patient may thenbe rewarmed as the SK is delivered. The rewarming step may beaccomplished by passing a warm saline solution as the working fluid.

EXAMPLE FOUR

(tPA)

Researchers have also investigated the effect of temperature on thefibrinolytic activity of tPA. Clots were treated with 2.5 μg/ml tPA andincubated at various temperatures (e.g., 37° C., 25° C., 1° C., 0° C.,and −8° C.). Plasminogen activation was relatively high at lowtemperatures (e.g., 0° C. or −8° C.) and was much less at highertemperatures. In other words, these researchers found that, for tPA,cooling to a hypothermic temperature from normal body temperatureincreased fibrinolytic activity.

As above, it is believed that such trends may be extended to patientswithout lack of accuracy. In this case, patients may be provided withtPA and may undergo hypothermia using an above device placed in anartery supplying blood to a thrombosed vessel. The catheter may includea separate lumen through which tPA may be delivered. A coolant orworking fluid may be supplied to the cooling catheter, causing thecatheter and the adjacent blood to cool. This cooling step may includethe step of inducing turbulence in the blood flowing in the vesseland/or in the working fluid. tPA may be delivered through the separatedrug delivery lumen. In this case, the patient may not be rewarmed untilthe drug delivery is complete, or until the thrombus is dissolved.

EXAMPLE FIVE

(tPA)

Researchers have further investigated the effect of temperature on thefibrinolytic activity of tPA. Clots were treated with tPA inconcentrations of 0.3 μg/ml, 1.0 μg/ml, and 3.0 μg/ml and incubated atvarious temperatures from 24° C. to 40° C. The amount of clot lysiscorrelated with temperature at all concentrations. However, contrary tothe results indicated in Example Four, the amount of clot lysis at lowertemperatures was less than that at higher temperatures. It isconjectured that heating may have enhanced the activation of plasminogenby the tPA, and that such heating may have a similar effect in patients.This general enhancement has also been seen in UK and SK systems.

Further research is clearly necessary to determine the optimalprocedure. In any case, an embodiment of the method of the invention maybe employed to advantageously perform either heating or cooling in animproved way. To enhance the activation of plasminogen by tPA, a warmsaline solution may be provided in a catheter of the type describedabove. The warm saline solution transfers heat to the blood at a heattransfer element. An appropriate temperature range for the warm salinesolution at a point within the heat transfer element may be about 38° C.to 74° C.

EXAMPLE SIX

(UK)

Researchers have also investigated the effect of temperature on thefibrinolytic activity of UK. In one such effort, clots were treated witha mixture of UK at temperatures of 4° C. and 28° C. A certain amount offibrinolytic activity was induced by the introduction of the UK to theclots. Heating to 28° C. caused a second phase of activation, resultingin complete conversion of all plasminogen to plasmin, and thus increasedfibrinolytic activity. In other words, heating from a very lowtemperature (4° C.) to a hypothermic temperature (28° C.) increased clotlysing. As above, it is believed that such trends may be extended topatients. As may be noted, this Example may be analogous to that ofExample Three because of the rewarming step; a similar procedure may beemployed to perform the procedure on patients.

The above examples indicate how drugs may be combined withtemperature-altering devices as, e.g. are disclosed above, to providesimultaneous cooling and thrombolysis. This combination provides a powerdual therapy which may be advantageously employed to aggressively treatstroke and other similar body insults. When dual therapies are employed,a cooling catheter may be inserted in one femoral artery for transit tothe brain for neural protection. Of course, a heating catheter would beemployed if a temperature rise were desired. Another catheter mayprovide the drug delivery. Alternatively, the heating or coolingcatheter may have disposed therein a lumen for drug delivery. Forexample, the lumen may be coaxial with the catheter and may be disposedalong the centerline of the catheter and heat transfer element.Alternatively, the lumen may be disposed along one portion of the wallof the outlet lumen. The drug delivery lumen may have an outlet at a tipof the heat transfer element. Examples of such catheters are disclosedin U.S. patent application Ser. No. 09/215,040, filed Dec. 16, 1998, andentitled “method and Device for Applications of Selective OrganCooling”, the entirety of which is incorporated by reference herein.These drug delivery catheters are particularly useful in dispensing thedrug or enzyme regionally, into a blood vessel containing the thrombusor into a blood vessel in fluid communication with the thrombosed bloodvessel.

The above examples have used known drugs. However, for all of the aboveand for similar techniques, an appropriate isoform of an enzyme may beemployed to allow enzymatic activity at temperatures other than nonnalbody temperature. One way to choose appropriate isoforms for theseenzymes is by searching for the same in cold climates. For example, SKis a bacterial enzyme. Bacteria live in many different temperatureenvironments. It is common to find or select an enzyme for a certainprocess or temperature by finding bacteria that live in environmentshaving the desired temperature.

As another example, the polymerase chain reaction is a polynucleotideamplification process that requires an enzyme capable of surviving hightemperatures. These enzymes were located in bacteria living in hotsprings and thermal vents on the sea floor. Therefore, it is likely thatcertain bacteria that live in room temperature environments orarctic-like environments will have enzymes similar to those desired,i.e., SK that can survive hypothermic environments. tPA and UK, on theother hand, are recombinant forms of human enzymes. As such, tPA and UKcould be genetically altered to maintain their activity at lowertemperatures. For example, the protein backbone could be changed toyield higher tPA or UK activity at lower temperatures.

Such “temperature-specific” enzymes or drugs may be advantageously usedto localize the effect of the enzymes or drugs. Some enzymes or drugsare considered to have risks associated with their use due to total bodyeffects. For example, some thrombolytic drugs are provided onlysparingly because of the risk of hemorrhage. This risk is presentbecause current drugs are active at a working temperature which iswithin the blood temperature range of the vascular system, and becausethe drugs pervade the entire vascular system. The blood temperaturerange of the vascular system is referred to here as being within a firsttemperature range and as having an average temperature at a firsttemperature. Drugs provided to lyse thrombi also reduce clottingthroughout the vascular system, increasing the risk of hemorrhage. Ofcourse, such effects are not limited to thrombolytic drugs.

The invention provides a way to reduce such total body risks. Asdiscussed above, an appropriate isoform of an enzyme may be employed toallow enzymatic activity at temperatures other than within a normal bodytemperature range, e.g., the first temperature range described above. Inother words, for cooling, an enzyme may be found with a workingtemperature range at a hypothermic temperature. Such an enzyme may notwork within the above-described first temperature range. For example, athrombolytic isoform may lyse clots where the blood temperature ishypothermic but may not produce fibrinolytic effects where the bloodtemperature is not hypothermic.

This type of drug or enzyme may be advantageously used in the presentinvention. For example, a heat transfer element may be placed in thevasculature upstream of a vicinity in which a clot has formed. The heattransfer element may be used to cool the blood flowing to the vicinityso that the blood in the vicinity achieves a hypothermic temperature. Anisoform of a thrombolytic drug may be delivered to the vicinity, theisoform having a working temperature at the hypothermic temperature. Theisoform of the thrombolytic drug may then act to lyse the clot. Thethrombolytic drug does not produce fibrinolytic activity in portions ofthe vasculature that are not at the hypothermic temperature, i.e., therest of the body. An advantage to this method is that even very strongthrombolytics may be used to effectively lyse clots, with significantlyless concern about the above-described fibrinolytic side effectsthroughout the remainder of the body.

While the method of the invention has been described with respect tospecific devices and techniques which may be used to cool blood, othertechniques or devices may also be employed. The embodiments of themethod of the invention may advantageously employ the turbulenceinducing devices and techniques disclosed above to enhance the heattransfer and thus the heating or cooling of the blood.

Furthermore, the invention has been described predominantly with respectto a particular lysing system: the lysing of a blood clot in a bloodvessel such as is caused by stroke or myocardial infarction. However,the methods of the invention can be equally applied to altering theactivity of any enzyme relative to its activity at normal temperatures.Furthermore, the invention may be applied to cooling solids, such asvolumes of tissue, rather than blood flows or static volumes of blood.Moreover, the invention can be applied to heating blood or tissue,especially when such heating advantageously enhances desired activity ina specific enzyme.

The invention has also been described with respect to certain drugtherapies. It will be clear to one of skill in the art that variousother drugs may be employed in the method of the invention, so long asthey have characteristics similar to those described above. Accordingly,the invention is limited only by the scope of the appended claims.

What is claimed is:
 1. A method of localizing a drug action, the drugpresent throughout a vascular system, the localization occurring towithin a volume of blood in a blood vessel, the vascular system havingan initial temperature substantially within a first temperature range,comprising: delivering a temperature-specific enzyme throughout avascular system including a volume of blood in a blood vessel, thetemperature-specific enzyme having a working temperature within aprespecified temperature range that does not substantially overlap thefirst temperature range; delivering a heat transfer element to a bloodvessel in fluid communication with the volume of blood; and adjustingthe temperature of the heat transfer element by passing a working fluidtherethrough such that the volume of blood in the blood vessel is heatedor cooled to the prespecified temperature range, such that the action ofthe temperature-specific enzyme is substantially limited to the volumeof blood heated or cooled.
 2. The method of claim 1, wherein theadjusting includes inducing mixing in the blood to enhance a heattransfer rate.
 3. The method of claim 2, wherein the adjusting furtherincludes inducing mixing in the working fluid flowing through the heattransfer element.
 4. A method of localizing a drug action tosubstantially within a volume of blood in a blood vessel, the vascularsystem having an initial temperature substantially within a firsttemperature range, comprising: delivering a temperature-specific enzymeto a volume of blood in a blood vessel, the temperature-specific enzymehaving a working temperature within a prespecified temperature rangethat does not substantially overlap the first temperature range;delivering a heat transfer element to a blood vessel in fluidcommunication with the volume of blood; and adjusting the temperature ofthe heat transfer element by passing a working fluid therethrough suchthat the volume of blood in the blood vessel is heated or cooled to theprespecified temperature range, such that the action of thetemperature-specific enzyme is substantially limited to the volume ofblood heated or cooled.
 5. The method of claim 4, wherein the deliveringincludes injecting the temperature-specific enzyme intravenously.
 6. Themethod of claim 4, wherein the delivering includes injecting thetemperature-specific enzyme through a lumen adjacent the heat transferelement.
 7. The method of claim 4, wherein the delivering includesinjecting the temperature-specific enzyme through a tip of the heattransfer element.